The chromatography technique is widely used in different forms for separating chemical and biological substances and there are many applications in compound preparation, purification and analysis. Liquid chromatography is of particular importance in the pharmaceutical and biological industries for the preparation, purification and analysis of proteins, peptides and nucleic acids.
A typical liquid chromatography apparatus has an upright housing in which a bed of packing material, which is usually particulate in nature and consists of a porous medium, rests against a permeable retaining layer. A liquid mobile phase enters through an inlet, for example at the end of an adaptor rod which has an elongated extension within the column. The liquid mobile phase thereafter enters a distributor plate which distributes the liquid mobile phase through a porous, perforated filter, mesh, frit or net, which together with the distributor plate is arranged on an adaptor. The liquid mobile phase thereafter moves through the bed of packing material and is finally removed via an outlet, typically through a second filter, mesh, frit or net and a second distributor plate.
Columns used in liquid chromatography typically comprise a tubular body enclosing the porous chromatography medium through which the carrier liquid or mobile phase flows, with separation of substances or analytes taking place between the mobile phase and solid phase of the porous medium. Typically, the porous medium is enclosed in the column as a packed bed, generally formed by consolidating a suspension of discrete particles, known as slurry that is pumped, poured or sucked into the column, usually from a bore or nozzle located at a tubular housing or at one end of the column. The production of a stable, even bed is often critical to the final separation process.
Conventional distribution systems for use in liquid chromatography comprise a distributor plate attached to the net. The distributor plate comprises channels arranged in a pattern to substantially uniform distribute the fluid over the plate. The distributor plate is perforated with holes or openings which lead the fluid from the channels and uniformly into the packed bed.
During the chromatography process the packed bed may be damaged and fines may occur in the column. After several chromatography cycles the fines may clog the net or nets in the column, which may result in higher back pressure and lower process efficiency. Therefore, maintenance of the chromatography columns must be conducted frequently and the nets or filters must be replaced after a number of cycles.
The backing plate or the lowermost, second end unit of the chromatography columns generally acts as a support for the column, being itself supported on legs or some other stand arrangement positioned on the floor which allows clearance for outlet pipe work projecting beneath the column.
When such a column requires maintenance to, or cleaning of, internal components, such as the valves, seals, meshes/screens/filters, distribution systems etc., heavy lifting gear such as a crane or hoist is necessary to lift the upper end/adaptor assembly away from the column tube and the column tube away from the lower end/base assembly as these assemblies can weigh in excess of three tons. The use of heavy overhead lifting equipment to disassemble the column in order to carry out internal maintenance is not desirable. Operator safety is obviously a concern when heavy equipment is lifted overhead and technicians exposed below. Furthermore, alignment structures are required to keep the column and its base/adaptor assemblies axially aligned as they are separated from each other, to avoid damage to the precision components.
The presence of such alignment and lifting structures imposes significant obstructions around the tube and need to be carefully laid out to provide sufficient clearance at some point of the circumference for insertion/removal of the internal components. Furthermore, the requirement to use heavy lifting equipment imposes constraints on housing such columns, sufficient overhead space and support being required to accommodate hoists or cranes. As many chromatography columns are now run in “clean” environments under GMP, to avoid microbiological contamination, where it is extremely difficult to accommodate overhead equipment, the requirement of moving the column to another room for disassembly and maintenance is problematic. This problem is exacerbated by the need to clean and verify the column before returning it for use to the clean environment. The presence of hoists or cranes in GMP facilities used for biopharmaceutical manufacturing is thus highly undesirable for the above mentioned reasons, together with the fact that these machines shed particulate matter, in the form of dirt, during their operation and maintenance.
U.S. Pat. No. 6,736,974 addresses some of the above problems by providing a column which is capable of lifting the adaptor assembly above the column tube and/or raising the column tube above the base assembly by means of an hydraulic system which is integral to the column.
However, the system described in U.S. Pat. No. 6,736,974 has significant disadvantages associated with it by virtue of its design. As can be seen from FIGS. 4 and 5 of U.S. Pat. No. 6,736,974 and described in column 4, lines 63-66 of that document, in order to remove the distributor plate (31) and/or filter/mesh (28/60) from the interior of the column, the operator must work within the centre of the drum (18) to access and remove the fixing nut (30) which secures these component parts. As industrial columns typically have diameters ranging from about 200 mm to 2000 millimeters, this means that the operator must work below a suspended or supported load to unscrew the nut. This clearly poses a significant safety risk to the operator, particularly where the operator's arm or head is exposed below the suspended or supported load.
Furthermore, once the column tube/cylinder or adaptor assembly has been raised from the base assembly or tube, respectively, removal of the heavy bed support and/or distributor from the column can only be accomplished by tilting the bed support or distributor at an angle to negotiate the hydraulic drive pistons or safety rods. This can clearly be seen from, for example, FIGS. 3, 4 and 5 in which the distance between any two safety rods (69) or between any two hydraulic pistons (36) is less than the diameter of the mesh/filter (28/60) or distributor plate (31). The same problem would exist for the base or adaptor bed support (not shown).
Removal of these internal components, which could weigh in excess of 100 kg, requires considerable manhandling by the operator and necessitates their being exposed below the suspended column or adaptor assembly. Once again, this represents a significant safety risk for the operator.
The task of physically removing the heavy bed support or distributor, as described in U.S. Pat. No. 6,736,974, must be carried out by an operator, there being no disclosure of the use of any lifting aid to assist in this task. The configuration of the hydraulic pistons and the safety rods, and the need to tilt the bed support and/or distributor in order to avoid hitting these supporting structures in withdrawing these components from the column, would require the design of a bespoke lifting device.
Document WO 2005/056156 also discloses a column which can be accessed for maintenance without the need for a crane or hoist. The column is designed such that the tube and the base assembly can be separated by means of hydraulic drive cylinders to provide an access space between them to conduct maintenance or service on the base assembly. The piston of the adaptor assembly can be advanced through the column tube to expose it at the open end of the column tube, i.e. in the space between the tube and the base assembly, for maintenance. However, as is evident from this document (for example, FIGS. 19 and 20 and related description on page 23) access to release the fastening screws retaining the bed support or mesh/filter in place is provided by the space between the tube and the base assembly. Removal of the bed support necessitates the operator being exposed to a suspended load while retaining screws are removed. Furthermore, the distance between any two drive cylinders for maintenance access is less than the diameter of the bed support, which requires the operator to manhandle and tilt the bed support when removing or replacing it. Maintenance of the column thus imposes a significant safety risk for the operator.
According to known chromatography columns the nets are welded or heat shrinked on the distributor plate, which distributor plate in turn is removably connected by fastening elements on the adaptor. Time and cost consuming operations are necessary in order to remove the clogged net from the distributor plate. Especially, when the chromatography column is of a large size the removal of the net from the distributor plate by using milling or turning machines is complicated. The replaced net must be welded or heat shrinked on the distributor plate before remounting on the adaptor. The chromatography column may not be used under a substantially period of time during the replacement of the nets. This may lead to production losses in the pharmaceutical and biological industries.
Notwithstanding the existence of such prior art chromatography column filters, there is a need to improve the maintenance methods available for chromatography columns by providing columns which are safer and easier for operators to use. Also, there is a need to reduce cost and time when conducting maintenance on chromatography columns. Also, there is a need to reduce complexity and to reduce needed floor space when conducting maintenance on chromatography columns.